放疗
1946年氮芥治疗 淋巴瘤获得成功
化疗
进入21世纪，分子靶向 治疗如火如荼
靶向治疗
肿瘤免疫治疗具有特异性和靶向性，一直为临床医师高度关注，近年进 步显著，使得免疫治疗成为更具期待的领域
Confidential 2/21/2013
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1890s 1st CA vaccine developed (coley)
1990s Discovery of role of checkpoint s in CA
Renaissance phase 1997-
1997 1st mAB approved for CA
2011 1st checkpoi nt inhibitor approved for CA
1973 discovery of the dendritic cell(steinma n)
2014 2nd checkpoi nt inhibitor approved for C5A
美国《Science》杂志:
2013年六大值得关注的科学领域 单细胞测序 “普朗克”探测微波背景辐射 人类连接组计划 探索南极冰下世界 癌症免疫疗法 基础植物研究
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Breakthrough of year 2013
CTLA-4 and PD-1/PD-L1 checkpoint blockade for cancer treatment
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CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment
○ Immune checkpoint blockade includes agents targeting the negative regulators CTLA-4 and PD-1
○ CTLA-4 attenuates the early activation of naive and memory T cells in the lymph nodes
Agents targeting CTLA-4 include ipilimumab and tremelimumab
○ In contrast, PD-1 modulates the effector phase of T cell activity in peripheral tissues via interaction with PD-L1 and PD-L2 ○ Agents targeting PD-1 include nivolumab and MK-3475 ○ Agents targeting PD-L1 include MPDL3280A and MEDI4736
Confidential 2/21/2013
Kyi C, et al. FEBS Lett. 2014;588:368-376 10
Comparing CTLA-4 and PD-1
Biological function Expression on Major role
Ligands Mechanism of action
CTLA-4
Inhibitory receptor
T cells at the time of initial response to antigen (activated CD8+ T cells)
Regulates the early stage of T-cell activation
肺癌免疫Байду номын сангаас疗进展
Outline
1
Cancer Immunotherapy
2
Update of checkpoint Inhibitors in lung cancer therapy
3
Future Outlook
Confidential 2/21/2013
2
Outline
1
Cancer Immunotherapy
B7.1 (CD80) B7.2 (CD86)
After ligand binding: Binding with PI3K, phosphatases SHP-2 and PP2A Blockade of lipid-raft expression Blockade of microcluster formation
Key events in the history of cancer immunotherapy
Enthusiasm phase 1976-1985
Skepticism phase 1986-1992
1976 1st study with BCG in bladder CA
e
1985 1st study with adoptive T-ce ll transfer in CA
2
Update of checkpoint Inhibitors in lung cancer therapy
3
Future Outlook
Confidential 2/21/2013
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肿瘤免疫治疗—攻克肿瘤的新希望
人类抗击肿瘤的历史
1896年coley毒素 应用于临床
免疫治疗
1899年放疗治愈 第1例病人
1978 Discovery of tumor specific mABs
1986 IFNα(cytokin e) approved for CA
1992 Il2(Cytokine) approved for CA
2010 1st cellular immunot herapy approved for CA
PD-1
Inhibitory receptor
Activated T cells, B cells, NK cells TILs in different tumor types
Confidential 2/21/2013
Science. 2013 Dec 20;342(6165):1432-3
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Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle
8 Immunity. 39(1)25 July 2013, Pages 1–10